A Chemical Inhibitor of the Skp2/p300 Interaction that Promotes p53‐Mediated Apoptosis

Oh, Misook; Lee, Jihoon; Moon, Heejo; Hyun, Yu Jung; Lim, Hyun Suk

doi:10.1002/anie.201508716

Cited by 52 publications

(36 citation statements)

References 31 publications

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“…Cpd M1 binds to Skp2/p300 interface, thereby releasing p300 for p53 acetylation and activation but does not affect Skp2 proteolytic activities. 55 Since Skp2 stability is regulated by p300-mediated acetylation, cpd M1 also downregulates Skp2. 55 , 56 However, in vivo efficacy of cpd C2/C16/ C20, cpd A and cpd M1 remains unclear.…”

Section: Discussionmentioning

confidence: 99%

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Skp2 deficiency restricts the progression and stem cell features of castration-resistant prostate cancer by destabilizing Twist

Ruan

et al. 2017

Oncogene

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Castration-resistant prostate cancer (CRPC) remains a major clinical challenge due to the lack of effective targeted therapy for its treatment. The mechanism underlying how CRPC gains resistance towards hormone depletion and other forms of chemotherapy is poorly understood. Research on understanding the factors that drive these processes is desperately needed to generate new therapies to cure the disease. Here, we discovered a fundamental role of S-phase protein kinase 2 (Skp2) in the formation and progression of CRPC. In transgenic adenocarcinoma mouse prostate model, Skp2 depletion leads to a profound repression of prostate tumor growth and distal metastasis and substantially prolonged overall survival. We revealed that Skp2 regulates CRPC through Twist-mediated oncogenic functions including epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) acquisitions. Mechanistically, Skp2 interacted with Twist and promoted the non-degradative ubiquitination of Twist. Consequently, Skp2 stabilized Twist protein expression by preventing proteasomal degradation of Twist by β-TrCP. We found that Twist overexpression augments CSC self-renewal and population and that Skp2 inhibition reverts Twist’s effects on CSC regulation. Furthermore, genetically depleting or pharmacologically inactivating Skp2 synergistically re-sensitized CRPC cells towards chemotherapies such as paclitaxel or doxorubicin. Together, the current study uncovering Skp2-mediated Twist stabilization and oncogenic functions in CRPC offers new knowledge on how CRPC progresses and acquires chemoresistance during tumor progression. It provides prove-of principle that Skp2 targeting is a promising approach to combat metastatic CRPC by targeting Twist and CSCs.

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Section: Discussionmentioning

confidence: 99%

“… 55 Since Skp2 stability is regulated by p300-mediated acetylation, cpd M1 also downregulates Skp2. 55 , 56 However, in vivo efficacy of cpd C2/C16/ C20, cpd A and cpd M1 remains unclear. Further studies are required to characterize their effects on tumor formation.…”

Section: Discussionmentioning

confidence: 99%

Skp2 deficiency restricts the progression and stem cell features of castration-resistant prostate cancer by destabilizing Twist

Ruan

et al. 2017

Oncogene

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“…In turn, Skp2 is acetylated and stabilized leading to positive regulation of its oncogenic function [48]. Thus the development of inhibitors to disrupt the Skp2/p300 interaction and promote p53-mediated apoptosis is proposed to represent an effective way for treating Skp2 driven cancers [49].…”

Section: P300/cbp: P300 and Creb-binding Proteinmentioning

confidence: 99%

Epigenetic Modulation Using Small Molecules - Targeting Histone Acetyltransferases in Disease

Richters

Koehler

2017

CMC

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Histone acetyltransferases (HATs) are epigenetic drivers that catalyze the acetyl transfer from acetyl-CoA to lysines of both histone and non-histone substrates and thereby induce transcription either by chromatin remodeling or direct transcription factor activation. Histone deacetylases (HDACs) conduct the reverse reaction to counter HAT activity. Physiological processes such as cell cycle progression or apoptosis require a thoroughly balanced equilibrium of the interplay between acetylation and deacetylation processes to maintain or, if required, alter the global acetylome status. Aberrant HAT activity has recently been demonstrated to play a crucial role in the progression of various diseases such as prostate, lung, and colon cancers as well as glioblastomas and neurodegenerative diseases. Recent investigations have aimed for the identification of HAT modulators to further decipher the complexity of acetyl transferase related signaling cascades and discover potential leads for drug design approaches. HDACs have been extensively characterized and targeted by small molecules, including four FDA-approved HDAC inhibitors; in contrast, HATs have not been active targets for therapeutic development. This review will summarize the status of HAT associated diseases and the arsenal of currently known and available HAT inhibitors with respect to their discovery, further improvements, and current applications.

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“…H2A.Z1, an isoform of H2A.Z, is upregulated in both HCC specimens and cell lines, and depletion of H2A.Z1 induces the expression of cell cycle inhibitors cyclin-dependent kinase inhibitor 1A (CDKN1A, also known as p21) and cyclin-dependent kinase inhibitor 1B (CDKN1B, also known as p27) in HCC ( 17 ). S-phase kinase-associated protein 2 (Skp2) is part of the E3 ubiquitin ligase complex that regulates many substrate proteins, including p27 and p21, through ubiquitination ( 18 ). This protein is encoded by skp2 , an established proto-oncogene in many cancers that promotes cancer progression and metastasis ( 19 , 20 ).…”

Section: Introductionmentioning

confidence: 99%

H2A.Z regulates tumorigenesis, metastasis and sensitivity to cisplatin in intrahepatic cholangiocarcinoma

et al. 2018

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Intrahepatic cholangiocarcinoma (ICC) is a fatal, malignant tumor of the liver; effective diagnostic biomarkers and therapeutic targets for ICC have not been identified yet. High expression of H2A histone family member Z (H2A.Z) is a high-risk factor for poor prognosis in patients with breast cancer and primary hepatocellular cancer. However, the significance of H2A.Z and its expression in ICC remains unknown. The present study demonstrated that H2A.Z is overexpressed in ICC and expression of H2A.Z correlated with poor prognosis in patients with ICC. H2A.Z regulated cell proliferation in vitro and in vivo via H2A.Z/S-phase kinase-associated protein 2/p27/p21 signaling. Inhibition of H2A.Z reduced cell proliferation and induced apoptosis in ICC. In addition, downregulation of H2AZ reduced tumor metastasis by repressing epithelial-mesenchymal transition and enhanced the antitumor effects of cisplatin in the treatment of ICC. Overall, H2A.Z promoted cell proliferation and epithelial-mesenchymal transition in ICC, suggesting that H2A.Z may be a novel biomarker and therapeutic target for ICC.

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A Chemical Inhibitor of the Skp2/p300 Interaction that Promotes p53‐Mediated Apoptosis

Cited by 52 publications

References 31 publications

Skp2 deficiency restricts the progression and stem cell features of castration-resistant prostate cancer by destabilizing Twist

Skp2 deficiency restricts the progression and stem cell features of castration-resistant prostate cancer by destabilizing Twist

Epigenetic Modulation Using Small Molecules - Targeting Histone Acetyltransferases in Disease

H2A.Z regulates tumorigenesis, metastasis and sensitivity to cisplatin in intrahepatic cholangiocarcinoma

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